MDM2 SNP309 Accelerates Tumor Formation in a Gender-Specific and Hormone-Dependent Manner

Abstract

The importance of the p53 stress response pathway in the suppression of tumor formation is well documented. In a previous report, a single nucleotide polymorphism (SNP309 T/G) was found in the promoter of the MDM2 gene resulting in higher levels of MDM2 RNA and protein and, consequently, in the attenuation of the p53 pathway both in vitro and in vivo. As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a welldescribed cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans. Data obtained from patients with three different sporadic cancers, from four independent case studies, support this hypothesis, providing an example for the genetic basis of gender differences in cancer and showing that the genotype at a specific locus can affect how hormones, like estrogen, affect tumorigenesis in humans.

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans

“…In fact, the ER was shown to bind to this region of the promoter in vivo (Kinyamu and Archer, 2003). Given that ER binds to the same region of the MDM2 promoter that harbors the SNP309 locus, and that the G-allele of SNP309 was shown to alter the affinity of a well-characterized co-transcriptional activator for multiple hormone receptors, including ER, namely Sp1 (Khan et al, 2003;Petz et al, 2004;Stoner et al, 2004), a recent report reasoned that the estrogensignaling pathway could affect how the SNP309 locus influences MDM2 transcription, and, therefore, tumor formation in humans (Bond et al, 2006a).…”

“…In this report, the data suggest that an active estrogen-signaling pathway is needed for the G-allele to accelerate tumor formation in humans (Bond et al, 2006a). This model was proposed based on the following observations made in patient populations diagnosed with either diffuse large B-cell lymphoma (DLBCL) or soft tissue sarcoma (STS) and in two patient populations diagnosed with invasive ductal carcinoma of the breast (IDC).…”

Genetic variants in germline TP53 and MDM2 SNP309 are not associated with early onset colorectal cancer

“…Since the discovery by Bond et al that SNP309 of the MDM2 gene can accelerate the onset of sarcoma and breast cancer in LFS patients, there have been several reports assessing the impact of the G allele of SNP309 on the age of CRC onset [16,[19][20][21]. The evidence from studies of sporadic CRCs is controversial, with most showing no overall effect but particular studies implicating the G allele in earlier age of onset among female patients or in patients with CRCs that are WT for p53.…”

“…Genetic variants in the p53 gene and its regulator MDM2 have been associated with increased susceptibility and early age of onset sarcoma, breast cancer, and adrenocortical cancer [15][16][17]. Recently, Wong and colleagues reported evidence from a family registry of Li-Fraumeni syndrome (LFS) kindreds indicating that germline mutations of p53 increase susceptibility to early onset CRC [18].…”

Characterization of cancer-associated missense mutations in MDM2

“…[31][32][33][34] Mouse embryonic fibroblasts derived from mice carrying humanized MDM2 SNP309G alleles express higher levels of MDM2 protein and grow faster than their wild-type counterparts. 34 This increased growth rate has been attributed to decreased p53 levels due to high turnover.…”